Active pharmaceutical ingredients (APIs) can be prepared in a variety of different forms, for example, chemical derivatives, solvates, hydrates, co-crystals, or salts. APIs may also be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states. By varying the form of an API, it is possible to vary the physical properties thereof. For instance, crystalline polymorphs typically have different solubilities such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical and pharmacological properties thereof.
Bendamustine, 4-{5-[Bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid:
was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 there, as the hydrochloride salt, under the tradename Cytostasan®. Since that time, it has been marketed in Germany under the tradename Ribomustin®. Ribomustin® is an amorphous, non-crystalline powder. Bendamustine Hydrochloride for injection is available in the United States under the tradename Treanda®.
Bendamustine is an alkylating agent that has been shown to have therapeutic utility in treating diseases such as chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer. It is supplied as a lyophilized cake of bendamustine hydrochloride salt Immediately before treatment, the lyophilized cake is dissolved in a pharmaceutically acceptable diluent, preferably Sodium Chloride for Injection.
It is generally desirable that injectable compositions be supplied as the free base form, rather than a salt form, to minimize any side effects that the counterion can produce. Previously described forms of bendamustine free base, however, were unstable and not suitable for commercial preparation, distribution, and administration. As a result, stable forms of bendamustine free base are needed.